ABSTRACT Autoimmune diseases affect millions of Americans and are chronic and often disabling illnesses with no cures. Current treatments help to prevent the symptoms of autoimmune disease, but there is a need for greater understanding of the underlying mechanisms of disease in order to facilitate improved treatments, and perhaps one day ? a cure. Current knowledge indicates that autoimmune disease arise due to a combination of genetic predispositions and environmental factors, but the etiology is not fully understood. We are studying one of the genetic factors that are implicated in human autoimmunity through both genome-wide association studies (GWAS) and recently identified patients with mutations in this gene. Using a newly established strain of mutant mice, we found a profound defect in immune tolerance, with high levels of autoreactive antibodies in the serum of very young mice. Antibodies are produced by B cells, and the presence of autoreactive antibodies indicates that this gene is necessary to control how B cells respond to antigen and to ensure tolerance to self. We propose to employ our mutant mice as a new model of autoimmunity to investigate the molecular mechanisms underlying the break of tolerance. We have preliminary data demonstrating lung infiltrates in this mouse models, and propose for the Fellowship candidate to investigate the cellular composition and subtype identity of the infiltrating cells. Furthermore, we have indications that gene isoform expression is important in the proper regulation of immune tolerance, and propose that the Fellowship candidate investigates the gene isoform expression across different stages of B-cell development. The work will be supplementing the work in the parental grant, and the candidate will be trained by current members of the laboratory research group.